Influenza viruses are constantly changing, requiring the reformulation of vaccines every year. Accurately estimating influenza vaccine effectiveness in preventing influenza infection is critical in order to evaluate the protection provided by annua, nationwide vaccination programs. Our long-term goal is to discover more advanced strategies to measure vaccine effectiveness, to potentially reduce the overall burden of influenza infection. The effectiveness of influenza vaccines with the ACIP recommended universal immunization strategy in the Scott and White Memorial Hospital -Temple Population Research Area (SWH-TPRA) adult source population will be systematically investigated. The objective of the proposed work is to explore strategies for measuring vaccine effectiveness against lab-confirmed influenza (VE-LCI) in adult inpatients, including the elderly, who have the highest hospitalization rates. This includes the identification, implementation and evaluation of innovative, feasible, and sustainable strategies for measuring VE-LCI in persons aged 18 years or older in acute inpatient care settings. The central hypothesis is that timely and efficient measurement of VE- LCI in adult inpatients is feasible and sustainable in the U.S. This hypothesis will be tested by pursuing three specific aims: 1) Identify innovative, feasible, and sustainable strategies to measure VE-LCI in a timely and efficient manner for persons ? 18 years admitted with an acute respiratory illness (ARI) in acute inpatient care settings, 2) Implement the above strategies to measure VE-LCI for adult inpatients with ARI, and 3) Evaluate the above strategies to measure VE-LCI for adult inpatients with ARI. To achieve these goals, VE-LCI will be determined in adults admitted to SWMH with ARI who test positive for influenza A and/or B by the real-time polymerase chain reaction (RT-PCR) assay. The odds of being vaccinated against influenza for PCR-confirmed cases will be compared to age-matched PCR-negative controls, after adjusting for confounders. During 2015- 2016 through 2019-2020, 300 patients and 800 adults admitted to SWMH with an ARI will be eligible to participate in the BSWH CDC VE-LCI adult inpatient study, respectively. Using a test-negative study design, VE-LCI for adult inpatients with ARI will be measured. Influenza immunization rates will be calculated for the RT-PCR confirmed cases and test negative controls, adjusting VE-LCI for confounders. The approach is innovative because effective measures of the public health impact of increasing influenza immunization on burden of illness will be defined. The proposed research is significant, because it will support improved understanding of timely and efficient measures of VE-LCI, which in turn will support the goal of reducing influenza-associated health burdens.